Both D- and L-phenylalanines are useful materials that can be obtained in various ways. However, to obtain the optically pure isomers, it is generally necessary to resolve a racemic mixture of the D- and L-isomers or derivatives thereof, and a particularly attractive way of obtaining them is the enzymatic resolution of a mixture of an N-acyl-D-phenylalanine ester and an N-acyl-L-phenylalanine ester, as taught in U.S. Pat. No. 4,262,092 (Bauer). To get the starting material for this enzymatic resolution, it would obviously be desirable to develop an efficient, economical method of preparing the racemic ester mixture in a single step. It would also be desirable to develop such a process that would be generally useful in the preparation of N-acylamino acid esters.
It is known that N-acylamino acids can be prepared by a variety of techniques, e.g., by the one-step processes of U.S. Pat. Nos. 3,766,266 (Wakamatsu et al.) and 4,264,515 (Stern et al.) and Japanese Patent Publication No. SHO 57-37585 (Yukawa et al.), but each of the patentees indicates that esters would not easily be formed by their processes.
Wakamatsu et al. teach a means of preparing N-acylamino acids by reacting an aldehyde with carbon monoxide and an acid amide in the presence of a carbonylation catalyst and preferably in a solvent. In column 3, lines 42-46, they indicate that the corresponding esters may be prepared by including an alcohol in the solvent. However, they also teach that secondary reactions may occur to cause cyclization or condensation of the reaction product, and they do not provide any exemplification of an esterification reaction.
Stern et al. teach a process similar to the process of Wakamatsu et al. except for the substitution of an olefinic compound for the aldehyde of Wakamatsu et al. These patentees also indicate in column 4, lines 62-66, that the use of certain alcohol solvents permits esters to be formed in the reaction, but they additionally teach that the use of those solvents should be avoided because of their disadvantageous effect on the reaction rate.
Yukawa et al. disclose the preparation of N-acylamino acids, such as N-acylphenylalanine, in a single step wherein an organic halide, such as benzyl chloride, is reacted with carbon monoxide, hydrogen, and an acid amide in the presence of a base and a cobalt catalyst. Their teachings indicate that this reaction can be conducted in water or in a mixture of water and a water-soluble solvent but that the use of such homogeneous solvent media is not as advantageous as their use of a two-phase solvent system consisting of a combination of water and a water-insoluble solvent, such as a hydrocarbon, ketone, higher alcohol, ether, nitrile, or ester. In Practical Example 1, their only disclosure of forming an N-acylamino acid ester, they teach the one-step preparation of N-acetylphenylalanine followed by a second step of converting that product to the methyl ester.